Working to Improve Survival Rates in Pancreatic Cancer

A Conversation With Ben Z. Stanger, MD, PhD

Although pancreatic cancer survival rates have slowly improved over the past few decades for all stages of pancreatic cancer combined, the 1-year rate is 20%, and the 5-year rate is about 9%. There is no single diagnostic test to detect pancreatic cancer, and less than 20% of tumors are confined to the pancreas at the time of diagnosis; in most cases, the malignancy has spread to the point where it is no longer resectable.

Ben Z. Stanger, MD, PhD

To shed light on the current state of pancreatic cancer research and treatment, The ASCO Post spoke with pancreatic cancer researcher Ben Z. Stanger, MD, PhD, the Hanna Wise Professor in Cancer Research at the Perelman School of Medicine at the University of Pennsylvania. He also is Director of the Penn Pancreatic Cancer Research Center, which consists of a group of clinicians, clinical researchers, and bench scientists unified in the goal of delivering better therapies to patients with pancreatic cancer through research. The central aim is to leverage what is learned about the basic biology of the tumor into drug development, ultimately reaching patients with pancreatic cancer.

Tumor Microenvironment

There’s been growing interest in the tumor micro-environment in the carcinogenic process in pancreatic cancer. Does your work take you into this area?

Absolutely. One of the things that makes pancreatic cancer so difficult to treat is that there are not a lot of molecular targets. The mutations that drive most pancreatic tumors, such as KRAS, TP53, CDKN2A, and SMAD4, do not currently respond to drugs, so we need to look elsewhere to be able to target this tumor. Plus, pancreatic tumors have a unique microenvironment, which is certainly an important target. We think about this environment as being very dense; the tumor cells actually comprise a smaller portion of the overall tumor than other cancer types. Many people consider all the fibroblasts and extracellular matrices a barrier to the delivery of chemotherapy, and there is some interest in finding ways to break that down to allow effective delivery of therapy.

We’re also quite interested in the unique metabolic mechanisms of the tumor. Most tumors are able to access the nutrients they need to be able to grow through angiogenesis, the recruitment of additional blood vessels. Pancreatic cancers are unique in that paradoxically they have a paucity of blood vessels. We liken pancreatic tumors to a desert, whereas many other tumor types are lush with blood vessels, living in the tropics. We refer to this as the “arid” microenvironment of the tumor. In other words, pancreatic tumors have figured out a way to survive with low concentrations of other types of nutrients, carbohydrates, and lipids. We are trying to understand how these tumors manage to survive under these conditions. And by understanding that, we hope to discover what vulnerabilities are inherent in the process and perhaps learn what drugs the tumor cells are susceptible to in these extreme conditions.

Cancer Cells and Fuel Sources

Your research looks at how responses to changes in oxygen availability impact the development of disease. Please talk a bit about that.

What we learned of biochemistry in medical school was how the cell takes glucose or other food sources and makes ATP. Most of the field of cancer metabolism has been wondering not so much about how do cancer cells use all of these fuel sources to make ATP, but rather how they use them as the building blocks to divert glucose and sugars and other lipids to make nucleic acids and more membranes to spur cell growth. Because of these arid or deprived conditions in pancreatic tumors, they must have some additional methodology to generate fuel sources. These tumors are very aggressive, but puzzlingly, the tumor cells do not divide rapidly, because of this lack of access to fuel sources that other tumors have. Instead, they are an insidious, unstoppable, terminator type of cancer cells.

Prospects for pancreatic cancer have improved, but they’re still poor; the disease currently has a 5-year survival rate of 9%. That’s up from 5% a few years ago, but it obviously means the therapies we’re using are not good enough. Therefore, we recommend that as many patients as possible engage in clinical trials. Some patients still believe that if they enter a clinical trial, they’re in effect serving as guinea pigs. The reality is that in most clinical trials they are going to receive standard therapy plus a novel therapy. We’re currently running several trials including adjuvant therapy in the postoperative setting, trials in locally advanced disease, as well as maintenance and biomarker studies.

It’s important for oncologists to understand that in the past, there has been a certain nihilism with pancreatic cancer; we need to put those days behind us so we can accrue as many eligible patients on clinical trials. At Penn Pancreatic Cancer Research Center, we try to get every patient who walks through the door matched with an appropriate trial. We call that philosophy hope for all stages.

In my lab, we have, among others, ongoing studies of molecular mechanisms of invasion and metastasis. In one project, we are identifying the mechanisms of EMT (epithelial-to-mesenchymal transition) in this model, providing the first molecular insights into this cellular shift in the context of a naturally progressing tumor. Another project is focusing on the cellular and molecular determinants of metastasis. We have found that tumors arising in a mouse model vary with respect to their ability to spread, and we hope to identify the genes that enable this spread so they may be targeted.

Immunotherapy: Focus of Research

Checkpoint inhibitors are taking center stage in how we think about treating cancer. Does immunotherapy offer promise in pancreatic cancer?

Yes. Immunotherapy has been a particular focus for researchers at Penn, and part of that work is taking place with the Parker Institute for Cancer Immunotherapy. So, we have a broad, dynamic portfolio that changes over time with the introduction of new clinical trials. For instance, there is increasing evidence to suggest that an inflammatory program establishes immune privilege in the tumor microenvironment. Indeed, pancreatic tumor cells might remain intrinsically sensitive to T-cell killing because they have never been exposed to Darwinian-like T-cell–selective pressure in vivo. It comes down to translational work, taking our knowledge from the lab and partnering with others such as industry to develop therapies that can enter the clinical trial setting.

Although I agree that checkpoint inhibitors are changing the way we’re approaching the treatment of cancer, to date, we have not had success with checkpoint inhibitors in pancreatic cancer. However, I would point out that even in tumors where a sizable number of patients do respond to checkpoint inhibitors, the majority still do not. So, across all cancer types, we still have a long way to go in our understanding about how to leverage these drugs to combat tumors. We have to be willing to return to the laboratory, find out how certain tumors evade the immune system, and deal with different metabolic challenges until we discover the linchpins of the disease. Then we can attack it with reliable therapies. ■

DISCLOSURE: Dr. Stanger has consulted for iTeos Therapeutics and has received a research grant from Boehringer Ingelheim.